Our Center has recently launched a new initiative to study CREB and the other molecular targets of interest to Projects 1-4 in brain reward regions of depressed humans on autopsy. This work focuses primarily on the NAc (nucleus accumbens) and VTA (ventraltegmental area). This endeavor represents a new Project 5 for the Center in this competitive renewal. We have already begun the collection of brains from depressed humans via the Dallas Brain Collection. Such collections have been proceeding at a rapid pace, which ensures the availability of an adequately large enough sample for meaningful analysis. The Project offers several powerful features for Center research. 1) We utilize the most stringent and rigorous measures of brain tissue quality, which is essential for postmortem brain studies. 2) Our focus on human brain reward regions complements most current efforts in the field, which have largely analyzed other brain circuits. 3) By focusing on the same genes and proteins that preclinical investigators study in rodent models of depression, the Project provides a major driving force for the critical translational mission of our Center. 4) We will examine these molecular targets both as a function of a diagnosis of depression (i.e., as seen in patients with major depression) and as a function of symptoms of depression (i.e., as seen across several diagnoses, including major depression, bipolar depression, and schizoaffective disorder with depression). 5) Alterations in molecular targets in the VTA and NAc will also be characterized as a function of developmental risk factors for depression (based on extensive history of the human subjects) and of particular genotypes recently implicated in genetic risk for depression. 6) The Project will study the possible influence of long-term antidepressant treatment on these molecular targets by treating rodents with prototypical agents for 6 months. We are very excited by the potential of this new initiative. We have demonstrated the feasibility of studying the various gene products of interest in human postmortem NAc and have already documented abnormalities in some of these products, which we know are altered in rodent depression models. At the same time, findings from the human tissue have provided new insight into regulation of these molecular pathways, which is guiding the preclinical research in the other Projects. Moreover, we have established the capability of carrying out advanced molecular analyses on human postmortem tissue, including, well beyond traditional DNA expression arrays, chromatin immunoprecipitation (ChIP), ChIP on chip, and microRNA assays in conjunction with the Chromatin and Gene Regulation Core. Together, the proposed studies will provide a uniquely powerful analysis of molecular pathologies in the human VTA-NAc associated with depression and its treatment.